Thelma E. Wiley

Differences in Viral Dynamics between Genotypes 1 and 2 of Hepatitis C Virus

Many studies have shown that patients infected with hepatitis C virus (HCV) of genotype 2 have better response to interferon (IFN)-alpha treatment than genotype 1 patients; however, the mechanisms responsible for this difference are not understood. In this study, viral dynamics during high-dose IFN induction treatment were compared between the genotypes. Patients in each group received 10 MU of IFN-alpha2b for 14 days, and HCV RNA levels were frequently determined. Nonlinear fitting, both individually for each patient and using a mixed-effects approach, of the viral kinetic data to a mathematical model of the IFN effect on HCV infection was performed. The antiviral effectiveness of IFN in blocking virus production, the free virion clearance rate, and the HCV-infected cell death rate were all significantly higher for genotype 2 patients than for genotype 1 patients. Thus, the better response rate of patients infected with HCV genotype 2 is multifactorial. This is the first finding of a difference in viral dynamics between subtypes of the same virus and demonstrates the importance of subtype-specific virus-host-drug interactions.

Hepatitis C infection in African Americans: its natural history and histological progression

OBJECTIVE:The aim of this retrospective analysis was to determine the natural history of hepatitis C virus infection in African Americans versus non-African Americans by evaluating the clinical, virological, and histological findings.METHODS:We examined in a retrospective manner the demographics, mode of infection, virological features, and histological progression of HCV infection in African Americans versus non-African Americans. There were 355 patients who met criteria based on adequate liver biopsy specimens and exclusion of other hepatic diseases.RESULTS:African Americans (n = 112) were significantly more likely to be infected with genotype 1 virus (88%) than were non-African Americans (n = 243; 67%; p ≤ 0.001). Baseline HCV RNA levels were similar, although baseline ALT values were significantly lower in African Americans (80.0 μl ± 5.5 vs 112.1 μl ± 6.2; p ≤ 0.001). African Americans were significantly older at the time of presentation and were significantly more likely to be women (p ≤ 0.02). In African Americans, there was a trend toward less cirrhosis (22% vs 30%; p ≤ 0.1) and significantly less piecemeal necrosis on liver biopsy. Non-African Americans had significantly higher fibrosis scores, ALT values, and piecemeal necrosis ratings, and tended to progress more rapidly to cirrhosis. This difference in histological progression between the two groups was not explained by differences in alcohol consumption.CONCLUSION:The lower ALT, piecemeal necrosis scores, and slower progression of fibrosis in African Americans may reflect less immunological recognition of HCV-infected liver cells.

The inaccuracy of duplex ultrasonography in predicting patency of transjugular intrahepatic portosystemic shunts

BACKGROUND & AIMS A prospective double-blinded study with preset sonographic criteria has not been performed to assess the accuracy of duplex ultrasonography in determining the patency of transjugular intrahepatic portosystemic shunts (TIPS). The purpose of this study was to determine the sensitivity and specificity of duplex ultrasonography in predicting shunt malfunction using accepted preset sonographic criteria. METHODS Sixty ultrasonographic and venographic follow-up comparisons were made on 38 cirrhotic patients who had undergone TIPS placement for variceal bleeding (n = 28) or intractable ascites (n = 10). Ultrasonographic results were analyzed by one of two board-certified ultrasonographers without knowledge of venographic findings. RESULTS Of the 31 occluded (n = 8) and stenotic (n = 23) shunts, ultrasonography accurately predicted a shunt malfunction (occlusion or stenosis) in only 11 studies and incorrectly predicted patency in 20. Compared with venography, ultrasonography had a sensitivity of 35% and a specificity of 83% in predicting TIPS stenosis or occlusion. CONCLUSIONS These results suggest that duplex sonography is not a sensitive test in predicting the presence of a hemodynamically significant stenosis and that shunt status should be assessed by venography and direct portal pressure measurements until a more reliable and proven noninvasive ultrasonographic criterion is devised.

Assessment of technical competence during ERCP training

BACKGROUND Successful performance of diagnostic and therapeutic ERCP requires skillful manipulation of the duodenoscope and accessories. The evaluation process for assessing competency is still in evolution. Recommendations for the number of examinations has ranged from 35 to 200, made without the benefit of prospective data. METHODS Pancreatic and common bile duct cannulation rates were prospectively recorded for 21 trainees and 9 proctors over 6 years in a large university-based training program. Trainee success rates were compared to those of the proctor and learning curves were constructed. RESULTS Trainees performed 641 examinations over 6 years. Each did an average of 31 examinations (range, 10 to 96). For both pancreatic duct and common bile duct cannulation, there was a rapid linear rise of the success curve extending up to the fortieth procedure. Pancreatic duct cannulation rates exceeded those of the common bile duct. CONCLUSIONS This is the first prospective evaluation of acquisition of skills in ERCP. Although the rapid rise of the learning curve ends at the fortieth examination, the 85% level of selective cannulation is not reached for the pancreas duct until the seventieth procedure and is not reached for the common bile duct even at 100 procedures. These data suggest a threshold of at least 100 procedures.

Effect of Obesity on Pharmacokinetics and Biologic Effect of Interferon-alpha in Hepatitis C

To examine potential adverse effects of obesityin reducing the response to interferon-alpha (IFN-alpha)in chronic hepatitis C (HCV), IFN-alpha and HCV RNAlevels in serum and the 2′,5′-oligoadenylatesynthetase (2-5 OAS) levels in peripheral bloodmononuclear cells (PBMC) were compared between six obeseand five nonobese patients before and after a single, 10mIU dose of IFN-alpha2b. There were nodifferences in the mean histologic activity index between thetwo groups. The maximal IFN concentration and the areaunder the serum IFN concentration-time curve were higherin nonobese patients. These two parameters were inversely correlated with body weight andbody surface area. No differences were found in the meanreduction in HCV RNA levels between the two groupsfollowing IFN-alpha. The maximal 2-5 OAS level after treatment divided by the pretreatment 2-5OAS level (2-5 OAS response ratio) was greater in thenonobese patients, suggesting stronger biologic responseupon exposure to exogenous IFN-alpha in nonobese patients.

Risk factors for failure to meet listing requirements in liver transplant candidates with alcoholic cirrhosis.

Background. The majority of liver transplant centers require a 6-month abstinence period before listing candidates for liver transplantation with alcoholic cirrhosis and a persistent sobriety thereafter. We attempted to identify risk factors for failure to comply with these requirements. Methods. Ninety-nine consecutive patients with alcoholic cirrhosis were referred for liver transplant evaluation between September 1996 and May 1998. The mean age was 49 years, 74% were male, and 54% were hepatitis C virus positive. To be listed, patients had to meet the following requirements. All patients received extensive psychosocial evaluations and were frequently monitored with random urine and blood alcohol tests; patients found positive were excluded or removed from the liver transplant waiting list. Detailed patient information was entered into a computerized database, and 36 discreet variables were analyzed in relation to success (patient listed and remained on the list) or failure (not listed or removed from the list based on noncompliance). Results. Forty-nine patients were successfully listed. Nineteen received a transplant, with a 95% 1-year patient and graft survival rate and 21% alcohol relapse rate after transplantation. Twenty-two patients had either medical contraindication and/or died before transplant listing. Twenty-four patients were never listed and four were removed from the list due to recurrent alcoholism, for a total of 28 failures. Our statistical analysis identified five significant risk factors for failure: (I) living arrangement (alone/family versus community/friend), P =0.006; (II) history of suicide ideation, P =0.03; (III) history of previous alcohol-related hospitalization, P =0.01; (IV) lack of previous alcoholic rehabilitation before transplant evaluation, P =0.001; and (V) failure to accept further alcoholic rehabilitation before orthotopic liver transplantation, P =0.01. Conclusions. Our experience confirms that transplantation can be extremely successful in properly selected patients with alcoholic cirrhosis. We identified several predictive psychosocial factors of early alcoholic recidivism in transplant candidates.

HEPATITIS C VIRAL DYNAMICS

It is apparent that the sooner the virus is cleared from the serum following IFN monotherapy, the better the sustained virologic response rates. It is also clear that in patients infected with HCV genotype 1a and 1b, standard dosages of IFN-alpha 2b (3 MU) administered three times a week are inadequate for a substantial and sustained lowering of HCV RNA serum levels. Understanding the kinetics and dynamics of HIV and HBV has greatly improved the understanding of the life cycle of these viruses and their response to therapy. Studies of the kinetics of HCV following initiation of IFN monotherapy have revealed that IFN-alpha 2b causes a rapid dose-dependent (3 < 5 < 10 = 15 MU) reduction in HCV RNA levels within 24 to 48 hours. This rapid exponential decline in RNA levels is best explained by an effect of IFN on viral production or release. The dose of other IFN products that maximally suppresses viral levels needs to be determined. Mathematical calculations reveal that HCV has a serum half-life of 3 hours and a viral production rate of 1.0 x 10(12) virions/d. After this rapid decline, there is a slower phase of viral decline that varies widely among patients and is attributed to the death rate of infected liver cells. The rate of decline of the second phase, which is probably mediated by immune clearance of infected liver cells, is the best viral kinetic predictor of early viral clearance. This kinetic information indicates that in patients infected with HCV genotype 1a or 1b, initial therapy with IFN should be daily and initial doses should be sufficient to reduce viral levels by more than 95% within 48 hours. Whether higher doses of IFN will alter or enhance the second phase of viral decline needs to be investigated. Also, the effect of ribavirin on IFN-mediated changes in HCV RNA levels needs to be investigated in carefully performed kinetics studies to better determine its mechanism of action. Defining the viral kinetics in patients infected with HCV genotype 2 or 3 and in patients who do not respond to IFN therapy will also improve the approach to therapy.

Is the presence of surgically treatable coronary artery disease a contraindication to liver transplantation

Advanced coronary artery disease has been traditionally considered an absolute contraindication to orthotopic liver transplantation where chronic liver failure significantly increases the surgical risk for coronary artery bypass grafting. Performing a simultaneous coronary artery bypass grafting and liver transplant is a theoretically attractive strategy in liver transplant candidates with coronary artery disease in need of revascularization. In the present article, we report a successful simultaneous coronary artery bypass grafting and orthotopic liver transplant with 1‐yr post‐operative follow‐up and we discuss the rationale for this approach. In selected cases, the presence of advanced coronary artery disease should not be considered an absolute contraindication to liver transplantation.

A pilot study of the combination of cyclosporin A and interferon alfacon-1 for the treatment of hepatitis C in previous nonresponder patients

Goals To evaluate the safety and efficacy of the combination of interferon and cyclosporine for the treatment of hepatitis C in previous nonresponder patients. Background Preliminary data indicated that adding the immunosuppressive agent cyclosporin A to interferon might improve response rates in patients with hepatitis C. Study Ten previous virologic nonresponders with genotype 1 infection were included. Treatment consisted of interferon alfacon-1, 15 &mgr;g/d, and cyclosporine, 100 mg twice daily, for 4 weeks. The dose of interferon alfacon-1 was then decreased to 15 &mgr;g three times weekly, and cyclosporine was reduced to 50 mg twice daily. Therapy was continued for 48 weeks unless viremia persisted at week 24. Results Three of 10 subjects had an on-treatment virologic response, although one had a breakthrough with recurrent viremia during treatment and two relapsed after therapy was completed. On treatment responders had significantly higher trough cyclosporine levels at week 4 compared with nonresponders (P = 0.025). Serum creatinine levels remained stable, and no patient developed diabetes. Triglyceride levels increased during treatment. Cyclosporine was dose reduced in two patients for hypertension. Conclusions Selected patients with hepatitis C tolerated therapy, including cyclosporine without severe or irreversible toxicity. Despite an association between higher cyclosporine levels and on-treatment response, the combination of cyclosporine and interferon was ineffective in producing a sustained response in previous nonresponder patients.

Combined coronary bypass and liver transplantation: technical considerations.

Combined coronary artery bypass grafting and orthotopic liver transplantation was carried out successfully in a 58-year-old man with angina pectoris and end-stage liver disease. To date, only 2 similar cases have been documented worldwide whereby the transplantation was performed either during cardiopulmonary bypass or with femoral-to-axillary venovenous bypass initiated at the termination of cardiopulmonary bypass. In this report we describe our experience with a simplified one-exposure approach for the combined operation using cardiopulmonary bypass in tandem with percutaneous femoral-to-right atrial venovenous bypass.